Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome.
Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome.
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增强的 mPGES-1 通过激活 NLRP3 炎症小体促进 PD 相关腹膜纤维化
DOI：
10.3389/fmed.2021.675363
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发表时间：
2021
影响因子：
3.9
通讯作者：
Dou X
中科院分区：
文献类型：
--
作者：
Luo Q;Hu Q;Zheng Q;Gong L;Su L;Ren B;Ju Y;Jia Z;Dou X
背景：微粒体前列腺素 E 合酶 1 (mPGES-1) 衍生的前列腺素 E2 (PGE2) 是炎症的主要介质。然而，mPGES-1在腹膜透析（PD）相关腹膜纤维化中的作用和机制尚未得到研究。材料和方法：检测PD患者腹膜组织中mPGES-1的表达以及透析液中PGE2、IL-1β和IL-18的水平。在大鼠腹膜间皮细胞 (RPMC) 中，研究了 mPGES-1 和 NLRP3 炎性体的调节和功能。采用Western blotting或实时定量PCR检测细胞外基质蛋白表达及NLRP3炎性小体成分。结果：在超滤失败（UFF）的PD患者中，腹膜中mPGES-1增强，且与腹膜纤维化程度相关。因此，腹腔内 PGE2 水平也与 PD 患者的 PD 持续时间、血清 C 反应蛋白水平和血清肌酐水平呈正相关。在 RPMC 中，高糖处理显着诱导 mPGES-1 表达和 PGE2 分泌，而不影响 mPGES-2 和 cPGES 表达。通过短发夹RNA抑制mPGES-1显着改善高糖诱导的RPMC细胞外基质蛋白的表达。此外，高葡萄糖显着激活 RPMC 中的 NLRP3 炎症小体，而 mPGES-1 抑制作用会减弱该炎症小体。此外，用siRNA沉默NLRP3可显着消除高葡萄糖处理的RPMC中细胞外基质蛋白的表达。最后，我们观察到帕金森病患者透析液中 IL-1β 和 IL-18 水平升高，与 PGE2 呈正相关。结论：这些数据表明，mPGES-1 衍生的 PGE2 通过激活 NLRP3 炎症小体在 PD 相关腹膜纤维化中发挥关键作用。靶向 mPGES-1 可能提供一种治疗 PD 期间腹膜纤维化的新策略。
Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated. Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR. Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2. Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.
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影响因子：
1.8
作者：
Martin EM;Jones SL
通讯作者：
Jones SL
影响因子：
4.9
作者：
McCann MR;Monemdjou R;Ghassemi-Kakroodi P;Fahmi H;Perez G;Liu S;Shi-Wen X;Parapuram SK;Kojima F;Denton CP;Abraham DJ;Martel-Pelletier J;Crofford LJ;Leask A;Kapoor M
通讯作者：
Kapoor M
影响因子：
13.6
作者：
Hautem, Nicolas;Morelle, Johann;Devuyst, Olivier
通讯作者：
Devuyst, Olivier
影响因子：
4.3
作者：
Strippoli R;Moreno-Vicente R;Battistelli C;Cicchini C;Noce V;Amicone L;Marchetti A;Del Pozo MA;Tripodi M
通讯作者：
Tripodi M
DOI：
10.1007/978-1-60761-849-2_5
发表时间：
2011-01-01
期刊：
DRUG SAFETY EVALUATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Ramos-Vara, Jose A.
通讯作者：
Ramos-Vara, Jose A.